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SUMMARY

Evette S. Radisky, Ph.D., has a research background in protein biochemistry and structural biology. Her long-term focus is on the molecular recognition between proteases and protein protease inhibitors.

Her research interests include many aspects of cancer biology, including the role of proteases in tumor progression and metastasis. A critical step in tumor development is the invasion of surrounding tissues, a process that can lead to development of distant metastases. Tumors accomplish this through increased activity of proteases that degrade cell-cell adhesion molecules and structural elements of the extracellular matrix.

In the microenvironment of normal tissues, proteolytic activity is modulated by endogenous inhibitors that bind to and inactivate proteases. In malignant tumors, the delicate balance between production, activation and inhibition of proteinases is often disturbed, leading to tumor cell invasion and dissemination.

The lab is developing cell culture and mouse models to elucidate mechanisms of mesotrypsin involvement in cancer, as well as employing structure-based engineering and library screening approaches to identify novel mesotrypsin inhibitors of potential therapeutic value.

Tissue inhibitors of metalloproteinases (TIMPs). The matrix metalloproteinase (MMP) family includes both tumor-promoting and protective enzymes, which means specificity is critical in developing strategies for therapeutic targeting of MMPs.

Dr. Radisky's team is studying the structure, specificity and biological function of the TIMP family of natural MMP-inhibiting proteins and developing methods for engineering therapeutic recombinant TIMPs with enhanced selectivity for cancer-promoting MMPs.

Stromelysins. The stromelysins MMP-3 and MMP-10 are highly homologous enzymes with similar substrate specificity, yet they reveal differential regulation and distinct roles in different cancers. Dr. Radisky's lab is studying the molecular determinants of their different pathological activities, which relate in part to their differential susceptibility to regulation by TIMPs.

Matrix metalloproteinase-9. This MMP, also known as gelatinase B, plays important roles in angiogenesis and metastasis of many tumor types. Using cell culture and mouse models, the team studies MMP-9 in breast cancer metastasis as a point of potential therapeutic intervention.

Serine protease inhibitor Kazal-type 1 (SPINK1). Also known as pancreatic secretory trypsin inhibitor, this natural protease inhibitor is responsible for preventing trypsin-catalyzed premature activation of zymogens within the pancreas, and its loss contributes to the pathogenesis of pancreatitis.

Surprisingly, upregulation of SPINK1 in a subset of prostate cancers stimulates tumor growth, invasion and metastasis. Dr. Radisky and her team are evaluating whether SPINK1 plays a similar role in the progression of ovarian cancers and investigating the molecular mechanisms by which this protease inhibitor stimulates malignancy.

Significance to patient care

Dr. Radisky's research focuses on proteases important for tumor invasion and metastasis, and centers on understanding the molecular interactions between these enzymes, their substrates and their endogenous inhibitors — with the aim of engineering inhibitors of improved potency and specificity for use as cancer therapeutics.

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